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Introduction Despite the effectiveness of combined antiretroviral therapy (ART), HIV infection remains a chronic condition characterized by persistent residual inflammation and immune activation, partly associated with HIV persistence and co-factors such as cytomegalovirus (CMV) coinfection. Evidence comparing the long-term immunological impact of different ART regimens remains limited and controversial. Long-acting (LA) injectable formulations may modulate the chronic immunoinflammatory state associated with HIV. We evaluated the dynamic changes in lymphoid immune activation and senescence markers in people with HIV(PWH) switching to long-acting cabotegravir/rilpivirine (CAB/RPV-LA), compared with PWH continuing oral ART, extending follow-up to 96 weeks.Methods T-cell immune activation(CD38 +HLA-DR+) and senescence(CD28−CD57+) were assessed at baseline (T0), and at weeks 4 (T4), 28 (T28), 48 (T48), 72 (T72), and, when available, 96 (T96) after switching to CAB/RPV-LA. A control group (CG) on daily oral ART was evaluated at T0 and T48. CMV-specific cellular and humoral immune responses were also measured.Results Thirty-eight PWH switching to CAB/RPV-LA and nine PWH-CG were enrolled ( table 1). Up to week 72, total CD4 levels remained stable, while CD8 levels decreased significantly at T72 versus T0 and T4. The CD4/CD8 ratio remained stable in both groups. Immune activation progressively declined in PWH-LA, with significant reductions in CD4 activation at T48 and T72 versus earlier time points and in CD8 activation at T72 versus T0 and T4. Immune senescence decreased in both compartments, with a significant reduction in CD8 senescence at T28, T48 and T72 compared to earlier time-points. Delta analysis confirmed a greater reduction in immune activation and senescence in PWH-LA compared to PWH-CG. CMV-specific responses showed a transient increase at T28 before returning to baseline at T48 and T72.At 96 weeks (n=15), total CD4 and CD8 counts, as well as the CD4/CD8 ratio, were increased compared with previous time points, improving trend observed at T72. CD4 activation and senescence and CD8 senescence were significantly reduced at T96 compared to T0, T4, T28, and T48, remaining stable relative to T72, which had already shown a marked decline. Polyfunctional CD4 and CD8 T cells, as well as total responding CD4 T cells, confirmed at T96 the favourable trend observed at T72. Notably, responding CD8 T cells further increased at T96 compared to T72 and all preceding time points. Plasma HIV-RNA and CMV-DNA remained undetectable in all subjects at all time points.Conclusions Switching to CAB/RPV-LA is associated with a sustained and progressive reduction of T-cell activation and senescence up to 96 weeks. These findings suggest a durable restoration of immune homeostasis beyond viral suppression. However, CMV coinfection remains a relevant contributor to residual immune dysregulation.Abstract OC41 Table 1